NICOTINAMIDE AS A RADIOSENSITIZER IN TUMORS AND NORMAL-TISSUES - THE IMPORTANCE OF DRUG DOSE AND TIMING

Background and purpose: Nicotinamide is a radiation sensitizer current ly undergoing clinical testing. This was an experimental study to dete rmine the importance of drug dose and time interval between drug admin istration and irradiation for radiosensitization. Materials and method s: Nicotinamide (50-500 mg/kg) was injected intraperitoneally into CDF 1 or C3H mice and drug plasma pharmacokinetics were determined by HPLC . Radiosensitization was measured in rumours and normal tissues after local irradiation. The tumours were a C3H mammary carcinoma, the KHT s arcoma and the SCCVII carcinoma. Tumour response was assessed using ei ther growth delay (C3H) or clonogenic survival (KHT/SCCVII). Normal ti ssue toxicities evaluated included early responding skin (development of moist desquamation of the foot) and late responding bladder (reserv oir function estimated by cystometry) and lung (ventilation rate measu red by plethysmography). Results: All nicotinamide peak plasma concent rations were seen within 30 min after injection. Irradiating tumours a t peak times resulted in enhancement ratios (ERs) of 1.27 (C3H), 1.75 (KHT) and 1.45 (SCCVII) with high nicotinamide doses and 1.27 (C3H), 1 .28 (KHT) and 1.36 (SCCVII) after giving clinically relevant doses (10 0-200 mg/kg). Lower ERs were observed when the time interval between d rug injection and irradiation was increased beyond the peak time. Irra diating normal tissues at peak times after injecting 100-200 mg/kg nic otinamide gave ERs of 1.20 (skin), 0.90 (bladder) and 1.02 (lung). Con clusions: Clinically achievable doses of nicotinamide will enhance tum our radiation damage while having minimal effects in normal tissues, b ut for the best tumour effect radiation should be given at the time of peak plasma drug concentrations. (C) 1997 Elsevier Science Ireland Lt d.